Differential effects of phosphatidylinositol-3/Akt-kinase inhibition on apoptotic sensitization to cytokines in LNCaP and PC-3 prostate cancer cells

Alterations in phosphatidylinositol 3'-kinase (PI3'-kinase) and Akt activat ion frequently occur in prostate cancer and may disrupt apoptotic induction by such cytokines as tumor necrosis factor (TNF) and TNF-related apoptosis -inducing ligand (TRAIL). To examine the role of PI3' phosphorylation in th e cellular response to cytokines, two prostate cancer cell lines with const itutively activated PI3'-kinase cascades (LNCaP and PC-3) were examined for direct sensitivity to cytokines, TNF or TRAIL alone failed to activate apo ptosis in either LNCaP or PC-3 cells, and drug-mediated inhibition of the P I3k/Akt cascade caused only minimal,activation of apoptosis in either cell line. Suppression of PI3'-kinase/Akt signaling markedly enhanced the apopto tic activity of both TNF and TRAIL in LNCaP cells but not in PC-3 cells. Ad enovirus-mediated PTEN/MMAC1 expression in LNCaP cells reduced Akt activati on, activated apoptosis, and sensitized cells to TNF but not to TRAIL. Toge ther, these results suggest that PI3'-kinase signaling inhibits both TNF-me diated and TRAIL-mediated apoptosis but may represent one of several apopto tic resistance mechanisms that inhibit cytokine-mediated killing of prostat e cancer cells.